Stimulant addiction remains an alarming concern in society, and new therapeutic directions for prevention and treatment are required. The purpose of the present proposal is to establish the Translational Center for Serotonin and Stimulant Addiction (TCSSA) to link human, animal and cellular model systems with target and drug discovery initiatives to achieve breakthrough therapeutic advances for stimulant addiction. The initial theme emerges from clinical evidence linking addiction vulnerability traits (e.g., impulsivity, cue reactivity) to plasticity of serotonin (5-HT) neural systems. This exploratory/developmental center will (1) create a new translational research engine through complimentary, reciprocal, and synergistic interactions among clinical neurobiology, preclinical psychopharmacology, molecular/cellular biology, and drug discovery initiatives;(2) build an enhanced framework to facilitate the mentoring and career development of junior scientists in translational research;(3) conduct three integrated Projects to test the hypothesis that endophenotypic traits (impulsivity, cue reactivity) associated with cocaine dependence emerge from an imbalance in 5-HT function which will be measured at genetic (e.g., 5-HT receptor gene polymorphisms), biological (e.g., 5-HT function in platelets and brain) and systems levels (e.g., response to treatment with 5- HT medications) and that this imbalance can be normalized through selective 5-HT ligands;(4) foster the high risk/exploratory goals of designing new, targeted serotonergic molecules for neurobiology and establishing their promise as new therapeutic modalities for addiction. With the development of this new translational sphere of research activity and the generation of new protocols and paradigms, we will demonstrate that neuronal remodeling in 5-HT systems can lead to behavioral recovery in addiction and jumpstart a new generation of discovery for anti-addiction therapeutics. The future TCSSA will mature from these beginnings, and will move toward the fundamental conceptualization of bridging from molecules and chemistry, through preclinical and human laboratory research, to clinical studies, and back. Lay Abstract. There is a pressing need to discover effective, accessible modalities for the treatment of stimulant addiction. Through clinical and laboratory methods, we will test the ability of existing medications and the potential for newly designed drugs to enhance abstinence in stimulant-dependent individuals.